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MBC in Press, published online ahead of print September 8, 2004
Mol. Biol. Cell 10.1091/mbc.E03-11-0853

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Submitted on November 27, 2003
Accepted on August 30, 2004

Susceptibility To Apoptosis in Insulin-like Growth Factor-I Receptor-deficient Brown Adipocytes

Angela M. Valverde,*{dagger} Cecilia Mur,* Michael Brownlee,{ddagger} and Manuel Benito*

*Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular II, Centro Mixto CSIC/UCM, Facultad de Farmacia, Ciudad Universitaria, 28040-Madrid, Spain; {ddagger}Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461

Monitoring Editor: Carl-Henrik Heldin

Fetal brown adipocytes are insulin-like growth factor-I (IGF-I) target cells. To assess the importance of the IGF-I receptor (IGF-IR) in brown adipocytes during fetal life, we have generated immortalized brown adipocyte cell lines from the IGF-IR-/- mice. Using this experimental model, we demonstrate that the lack of IGF-IR in fetal brown adipocytes increased the susceptibility to apoptosis induced by serum withdrawal. Culture of cells in the absence of serum and growth factors produced rapid DNA fragmentation (4 h) in IGF-IR-/- brown adipocytes, as compared with the wild-type (16 h). Consequently, cell viability was decreased more rapidly in fetal brown adipocytes in the absence of IGF-IR. Furthermore, caspase-3 activity was induced much earlier in cells lacking IGF-IR. At the molecular level, IGF-IR deficiency in fetal brown adipocytes altered the balance of the expression of several proapoptotic (Bcl-xS and Bim) and antiapoptotic (Bcl-2 and Bcl-xL) members of the Bcl-2 family. This imbalance was irreversible even though in IGF-IR reconstituted cells. Likewise, cytosolic cytochrome C levels increased rapidly in IGF-IR-deficient cells as compared with the wild-type. A rapid entry of Foxo1 into the nucleus accompanied by a rapid exit from the cytosol and an earlier activation of caspase-8 were observed in brown adipocytes lacking IGF-IR upon serum deprivation. Activation of caspase-8 was inhibited by 50% in both cell types by neutralizing anti-Fas-ligand antibody. Adenoviral infection of wild-type brown adipocytes with constitutively active Foxo1 (ADA) increased the expression of antiapoptotic genes, decreased Bcl-xL and induced caspase-8 and -3 activities, with the final outcome of DNA fragmentation. Up-regulation of UCP-1 expression in IGF-IR-deficient cells by transduction with PGC-1{alpha} or UCP-1 ameliorated caspase-3 activation, thereby retarding apoptosis. Finally, insulin treatment prevented apoptosis in both cell types. However, the survival effect of insulin on IGF-IR-/- brown adipocytes was elicited even in the absence of PI 3-kinase/Akt signaling. Thus, our results demonstrate for the first time the unique role of IGF-IR in maintaining the balance of death and survival in fetal brown adipocytes.

{dagger}Corresponding author. E-mail: valverde{at}farm.ucm.es




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